Process for producing 7β-substituted-aza-5αandrostan-3-ones

ABSTRACT

Described is a new process for producing 7β-substituted-4-aza-5α-androstan-3-ones and related compounds which are 5α-reductase inhibitors.

BACKGROUND OF THE INVENTION

The present invention is directed to a new process for preparing7β-substituted-4-aza-5α-androstan-3-ones and related compounds and theuse of such compounds as 5α-reductase inhibitors.

DESCRIPTION OF THE PRIOR ART

The art reveals that certain undesirable physiological manifestations,such as acne vulgaris, seborrhea, female hirsutism, male patternbaldness and benign prostatic hypertrophy, are the result ofhyperandrogenetic stimulation caused by an excessive accumulation oftestosterone or similar androgenic hormones in the metabolic system.Early attempts to provide a chemotherapeutic agent to counter theundesirable results of hyperandrogenicity resulted in the discovery ofseveral steroidal antiandrogens having undesirable hormonal activitiesof their own. The estrogens, for example, not only counteract the effectof the androgens but have a feminizing effect as well. Non-steroidalantiandrogens have also been developed, for example,4'-nitro-3'-trifluoromethylisobutyranilide. See Neri, et al., Endo.,Vol. 91, No. 2 (1972). However, these products, though devoid ofhormonal effects, are peripherally active, competing with the naturalandrogens for receptor sites, and hence have a tendency to feminize amale host or the male fetus of a female host.

It is now known in the art that the principal mediator of androgenicactivity in some target organs is 5α-dihydrotestosterone, and that it isformed locally in the target organ by the action oftestosterone-5α-reductase. It is also known that inhibitors oftestosterone-5α-reductase will serve to prevent or lessen symptoms ofhyperandrogenic stimulation.

A number of 4-aza steroid compounds are known in the art as 5α-reductaseinhibitors. For example, see U.S. Pat. Nos. 4,377,584, 4,220,775,4,859,681, 4,760,071 and the articles J. Med. Chem. 27, p. 1690-1701(1984) and J. Med. Chem. 29, 2998-2315 (1986) of Rasmusson, et al., U.S.Pat. Nos. 4,845,104 to Carlin, et al., and 4,732,897 to Cainelli, et al.which describe 4-aza-17β-substituted-5α-androstan-3-ones said to beuseful in the treatment of DHT-related hyperandrogenetic conditions.

However, despite the suggestion in the prior art that hyperandrogeneticdiseases are the result of a single 5α-reductase, there are reportsregarding the presence of other 5α-reductase isozymes in both rats andhumans. For example, in human prostate, Bruchovsky, et al. (See J. Clin.Endocrinol. Metab. 67, 806-816, 1988) and Hudson (see J. SteroidBiochem. 26, p 349-353, 1987) found different 5α-reductase activities inthe stromal and epithelial fractions. Additionally, Moore and Wilsondescribed two distinct human reductases with peaks of activities ateither pH 5.5 or pH 7-9. (See J. Biol. Chem. 251, 19, p. 5895-5900,1976.)

Recently, Andersson and Russell isolated a cDNA which encodes a ratliver 5α-reductase (see J. Biol. Chem. 264 pp. 16249-55 (1989). Theyfound a single mRNA which encodes both the liver and prostaticreductases of rats. The sequence of this rat gene was later used toselect a human prostatic cDNA encoding a 5α-reductase termed"5α-reductase 1". (See Proc. Nat'l. Acad. Sci. 87, p. 3640-3644, 1990.)

More recently, a second, more adundant reductase (5α-reductase 2) hasbeen cloned from human prostate with properties identified with the formfound in crude human prostatic extracts. (See Nature, 354, p. 159-161,1991.)

Further, "Syndromes of Androgen Resistance"--The Biology ofReproduction, Vol. 46, p. 168-173 (1992) by Jean O. Wilson indicatesthat the 5α-reductase 1 enzyme may be associated with hair follicles.

Thus, the art supports the existence of at least two genes for5α-reductase and two distinct isozymes of 5α-reductase in humans. Bothforms are present in prostatic tissue in which, 5α-reductase 2, is themore abundant, and the other isozyme, 5α-reductase 1, is believed to bemore abundant in scalp tissue.

In the treatment of hyperandrogenetic disease conditions, e.g. benignprostatic hyperplasia (BPH) it would be desirable to have one drugentity which is active against both enzymes 1 and 2 in the prostate tosubstantially inhibit dihydrotesterone (DHT) production. Alternatively,it would be desirable to have a drug entity which is highly selectivefor inhibiting the scalp associated enzyme 5α-reductase 1, for use intreating diseases of the skin and scalp, e.g. acne and alopecia. Thislatter drug could also be used in combination with PROSCAR®(finasteride) which is highly selective for the prostatic enzyme5α-reductase 2 for combination therapy in the treatment of BPH.

New processes are continuously being searched for which are moreefficient and environmentally acceptable for producing 7-betasubstituted androstane-3-ones, which are active against both alphareductase enzymes 1 and 2.

SUMMARY OF THE INVENTION

The present invention discloses a novel process for preparing7β-substituted-4-aza-5α-androstan-3-one compounds which are useful forinhibiting the 5α-reductase isozymes 1 and 2 and are particularlyeffective in selectively inhibiting the 5α-reductase-1 associated withthe scalp and dually inhibiting both isozymes 1 and 2 in the oral,parenteral or topical treatment of benign prostatic hyperplasia, acne,female hirsutism, male pattern baldness, androgenic alopecia,prostatitis, and the prevention and treatment of prostatic carcinoma.

In accordance with the present invention there is provided a processcomprising the step of:

a) contacting the compound IV, where Alk is ##STR1## C₁ -C₄ alkyl,allyl, and C₃ -C₆ cycloalkyl, and A is a substituent inert under thereaction conditions, with a reducing system comprised of: metalliclithium and liquid ammonia in an inert organic solvent therefor at atemperature in the range of about -45° to -78° C. for a sufficient timeto stereoselectively produce the 7-beta compound V: ##STR2##

Further provided in the process is the step of:

b) contacting compound V with a double bond isomerization agent in aninert organic solvent therefor, at a temperature of 40° to 65° C., underconditions in which the radical A is inert, for a sufficient time toform the isomerized compound VI. ##STR3##

Also provided in the process is the step of:

(c) contacting compound VI with an oxidizing agent in an inert solventtherefor, at a temperature in the range of 23° to 80° C., underconditions in which radical A is inert, for a sufficient time to formthe seco acid VII: ##STR4##

In addition, there is provided the step of:

(d) contacting the seco acid compound VII with an amine of the formula:R--NH₂, wherein R is H, C₁ -C₄ alkyl, benzyl or allyl, at a temperatureof from 100° to 200° C. in an inert solvent therefor, under conditionsin which A is inert, to form the 4-aza-steroid VIII: ##STR5##

Provided also in the process is the step of:

(e) contacting VIII with a platinum catalyst in an inert organicsolvent, at room temperature, under conditions where A is inert, for asufficient time to form the 7-Alk 4-aza steroid VII: ##STR6##

Specific embodiments of the process is where Alk is methyl; the reducingsystem is comprised of metallic lithium and liquid ammonia; the processis carried out in the temperature range which is -78° to -45° C.

Also provided is the overall process comprising the steps of:

a) contacting the compound IV, where Alk is ##STR7## C₁ -C₄ alkyl, allyland C₃ -C₆ cycloalkyl, and A is a substituent inert under the reactionconditions, with a reducing system comprised of: metallic lithium andliquid ammonia in an inert organic solvent therefor at a temperature inthe range of about -45° to -78° C. for a sufficient time tostereoselectively produce the 7-beta compound V: ##STR8##

b) contacting compound V with a double bond isomerization agent in aninert organic solvent therefor, at a temperature of 40° to 65° C., underconditions in which the radical A is inert, for a sufficient time toform the isomerized compound VI. ##STR9##

(c) contacting compound VI with an oxidizing agent in an inert solventtherefor, at a temperature in the range of 23° to 80° C., underconditions in which radical A is inert, for a sufficient time to formthe seco acid VII: ##STR10##

(d) contacting the seco acid compound VII with an amine of the formula:R--NH₂, wherein R is H, C₁ -C₄ alkyl, benzyl or allyl, at a temperatureof from 100° to 200° C. in an inert solvent therefor, under conditionsin which A is inert, to form the 4-aza-steroid VIII: ##STR11##

(e) contacting VIII with a platinum catalyst in an inert organicsolvent, at room temperature, under conditions where A is inert, for asufficient time to form the 7-Alk 4-aza steroid VII: ##STR12##

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

By the term "C₁ -C₄ alkyl" as used herein, is meant to include: e.g.methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl andt-butyl.

By the term "C₃ -C₆ cycloalkyl" as used herein is meant to includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The process of this invention is illustrated in the followingFlowsheets: ##STR13##

7-Beta Alkyl-17-A Series

The compounds produced by the instant invention also include a 7β alkylgroup, e.g. methyl, ethyl, isopropyl, t-butyl, allyl, where A is definedbelow, can be prepared by the procedure outlined in The GeneralFlowsheet.

The term "Alk" as used herein being the 7-beta substituent in theformula signifies C₁ -C₄ linear or branched alkyl, e.g. methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, andcycloalkyl.

The "Alk" substituent can be introduced onto the B ring of the 4-azasteroid generally by the application of an organometallic carbonyladdition reaction, e.g. the Grignard reaction in which the 7-carbonylgroup can be reacted with the Grignard reagent containing "Alk" as the Rradical in RMgX. Also applicable in the process are carbonyl additionreactions utilizing lithium and zinc organometallic reagents which areknown in the art.

The term "A" is the 17-substituent which can be any substituentpreferably inert and non-interfering under the particular reactionconditions of each step outlined in the following General Flowsheet.

The A group can also be a protected hydroxy or protected amino groupwhich undergoes the indicated reaction sequence and then is subsequentlyremoved, or it can also be removed during a particular step providing itdoes not interfere with the indicated reaction. For example, where A is17-0-TBDMS, i.e., t-butyl-dimethylsilyloxy, the silyl protecting groupcan be removed during e.g., the ring closure step of the seco acid VIIto the 4-aza steroid VIII, such that the subsequent steps are performedon the 17-OH compound. Also, the starting A group can be a precursor tothe finally desired A group and be converting thereto concurrently inone of the steps. For example, where A contains a double bond, e.g., astigmasterol analog, the double bond in the 17-side chain may also beoxidized during the seco acid formation in going form VI to VII.

Representative examples of the 17-A group include H, protected hydroxy,e.g. dimethyl-t-butyl silyloxy, hydroxy, protected amino, e.g.acetylamino, amino, C₁ -C₁₀ alkyl, e.g. methyl, ethyl, 6-methylhept-2-yl(cholestanyl 17-side chain), stigmasterol side chain, aryl substitutedC₁ -C₁₀ alkyl, e.g. omega-phenylpropyl, heteroaryl substituted C₁ -C₁₀alkyl, e.g. omega-(4-pyridyl)-butyl, carboxylic ester, e.g.carbomethoxy, carboxamide, e.g. N,N-diisopropyl carboxamide, carboxylicacid, carbamates, e.g. t-butylcarbonylamino ureas, e.g.n-t-butylcarbonylamino, ethers, e.g. n-butyloxy- and the like.

The starting materials for the process generally are the3-acetoxy-androst-5-enes which are known and available in the art.

As seen in the Flowsheet, using general formulas, where A is describedabove, the starting 3-acetoxy-androst-5-en-17-A I is oxidized to thecorresponding 5-en-7-one II by treatment with e.g. hydrogen t-butylperoxide and chromium hexacarbonyl in e.g. acetonitrile, at reflux.Other solvents which can be used include propionitrile, butyronitrile.The temperature for the reaction is generally carried out with range of40° to 85° C. and the reaction is carried out under dry conditions andgenerally requires about 24 hours for completion.

The Alk group, e.g. methyl, ethyl, allyl, phenyl, can be introduced atthis point by an organometallic carbonyl addition reaction, e.g.Grignard reaction using e.g., methyl, allyl or cycloalkyl magnesiumchloride in e.g., anhydrous THF at 0°-23° C. to produce the7-Alk-7-hydroxy adduct III. The Grignard reaction conditions areconventional and include the use of methyl magnesium chloride, ethylmagnesium bromide, allyl magnesium chloride, cyclopropyl magnesiumbromide, and the like. Other usable dry solvents include diethyl ether,dimethoxyethane, di-n-butyl ether. The reaction is conducted under dryconditions generally in the temperature range of 0° to 40° C. Generally,the reaction requires about 6 to 24 hours for completion. Otherorganometallic carbonyl addition reactions can be used.

The adduct III is then oxidized with e.g. aluminum isopropoxide andcyclohexanone (Oppenauer oxidation conditions) in e.g. refluxing toluenesolvent to produce the 7-alkyl-4,6-dien-3-one IV. Other reagents whichcan be used are aluminum ethoxide or aluminum t-butoxide. Other solventswhich can be used are methylethylketone and xylene. The temperaturerange is generally in the range of 60° to 120° C., the reaction carriedout under anhydrous conditions and generally requires about 2 to 24hours for completion.

The next step is a key step in which the Grignard adduct IV is reducedwith metallic lithium, liquid ammonia, THF and toluene at -78° C. tostereoselectively yield the 7-beta-alkyl-5-en-3-one V. Other metalswhich can be used in this reduction are: sodium, potassium, and calcium.Other amines which can be used are methylamine and ethylamine. Othersolvents which can be used are: n-butylether, and dimethoxyethane. Thereaction is generally carried out under anhydrous conditions in thetemperature range of 23° C. to -78° C. and requires about 2-10 hours togo to completion.

In the next step the delta-5 double bond is isomerized to the 4-ene VIby the use of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) in, e.g.refluxing tetrahydrofuran (THF) to produce 7-alkyl 4-en-3-one. Otherisomerization reagents which can be used include: diisopropylethylamineand DBN (Aldrich), being 1,5-diazabicyclo[4.3.0]non-5-ene. Othersolvents which can be used include: toluene, dimethylether. The reactionis generally carried out under dry conditions at a temperature range of40° to 65° C. and generally requires 1-2 hours for completion.

The A Ring is next cleaved by treatment with e.g. potassiumpermanganate, sodium periodate in e.g., t-butylalcohol at 80° C. toproduce the corresponding seco-acid VII. Other oxidation reagents whichcan be used include ruthenium tetraoxide and ozone. Other solvents whichcan be used are: CH₃ CN, CCl₄, MeOH and CH₂ Cl₂. The reaction generallyrequires about 2 to 4 hours to proceed to completion.

Treatment of the seco-acid with an appropriate amine e.g., methylaminehydrochloride and sodium acetate in ethylene glycol at 180° C., yieldse.g., the 4-methyl-4-aza-androst-5-en-3-one VIII. Other amines which canbe used are ethylamine, ammonium acetate, substituted benzylamines, e.g.4-methoxybenzylamine, and the like. Other solvents applicable in thereaction include: acetic acid, xylene. The reaction is generally carriedout at a temperature in the range of 100° to 200° C. and generallyrequires about 2-8 hours to proceed to completion.

Structure VIII in turn is catalytically hydrogenated with e.g., Pt, toreduce the 5-delta double bond to produce the 5α-hydrogen compound IX.The solvent for the reduction is usually acetic acid but also useful isEtOH. The catalysts for this hydrogenation also include Pd/C and noblemetals e.g. nickel. The hydrogenation is usually carried out in a shakerhydrogenation apparatus at room temperature under a H₂ pressure of 40 to2000 psig. and generally requires about 1-24 hours to proceed tocompletion.

The seco-acid VII can be similarly treated with ammonia generated fromammonium acetate to produce the corresponding N-H compound, X, which canthen be analogously treated as above with catalytic Pt in a hydrogenatmosphere to produce the corresponding 5α-4N-H compound XI.

Throughout this series of reactions, the 17-A group should be inert ornon-interfering to the individual reaction conditions for placing the7-substituent onto the steroid B ring. ##STR14##

7-Beta Alkyl-17-Oxy-Androstanes

The process of the instant invention is also applicable, e.g. where 17-Ais hydroxy or protected hydroxy. The appropriate 7β alkyl group, e.g.methyl, ethyl, isopropyl, can be introduced by the procedure outlined inFlowsheets A and B.

As seen in Flowsheet A, the 3-acetoxyandrost-5-en-17-one 1 is reactedwith sodium borohydride in a suitable solvent, e.g. ethanol, at -10° C.to stereo-specifically reduce the 17-ketone to the 17β-ol 2. The17-hydroxy group is protected with the TBS group (t-butyldimethylsilyl)by reacting TBS chloride with 2 in a suitable solvent, e.g. DMF in thepresence of the proton acceptor, e.g. imidazole, at room temperature, toform 3.

Following the hydroxy protection, this compound is oxidized in the sevenposition to the corresponding 5-en-7-one 4 by treatment of 3 withhydrogen t-butyl peroxide and chromium hexacarbonyl in e.g.acetonitrile, at reflux. The alkyl group, e.g. methyl, can be introducedat this point by a Grignard reaction using e.g., methyl magnesiumchloride in anhydrous THF at 0°-10° C. to produce the 7-methyl-7-hydroxyadduct 5. This Grignard product is then oxidized with aluminumisopropoxide and cyclohexanone (Oppenauer oxidation conditions) inrefluxing toluene solvent to produce the 7-methyl-4,6-dien-3-one 6. Thisin turn is reduced using metallic lithium, in liquid ammonia, THF andtoluene at -78° C. to selectively yield the 7-beta-methyl-5-en-3-one 7.In the next step the delta-5 double bond is isomerized to the 4-ene byuse of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) in refluxingtetrahydrofuran (THF) to produce the 4-en-3-one, 8. The A Ring is nextcleaved by treatment with potassium permanganate, sodium periodate int-butyl alcohol at 80° C. to produce the corresponding seco-acid 9.Treatment of the secoacid 9 with an appropriate amine e.g., methylaminehydrochloride and sodium acetate in ethylene glycol at 180° C., yieldsthe 4-aza-androst-5-en-3-one 10. The TBS protecting group is thenremoved e.g., by aqueous HF in acetonitrile at 0° C., to yield the 17-Balcohol 11. This in turn is selectively reduced to remove the 5-deltadouble bond to produce the 5α-hydrogen compound 12. ##STR15##

7-Beta-Ethyl-Cholestane Analogues

The 7-ethyl substituent is introduced into the cholestane series asillustrated in Flowsheets C and D by the same analogous procedure asdescribed in the General Flowsheets and A and B.

The starting cholesteryl acetate CA is available commercially (Aldrich).This is treated using the analogous chromium hexacarbonyl/hydrogent-butylperoxide/acetonitrile oxidation procedure (described in JCSPerkin Trans. 1985, p. 267 by A. J. Pearson) to yield the3-acetoxy-cholest-5-en-7-one 1a. This can be reacted with an alkylGrignard reagent, e.g. ethyl magnesium chloride to form the adduct 2a.This is oxidized under Oppenauer conditions to yield the dienone 3a,which then can undergo metal-ammonia reduction to yield the7β-ethyl-5-en-3-one, 4a. This is isomerized using DBU to the 4-en-3-one,5a, which is oxidized to open Ring A to yield the seco-acid 6a. This canbe treated with amines, e.g. methylamine, to yield the A-ring closed4-methyl-4-aza compound 7a. This in turn can be catalyticallyhydrogenated to yield the7-ethyl-5-alpha-4-methyl-4-aza-cholestan-3-one, 8a.

Similarly, by treatment of the seco-acid 6a with ammonium acetate/aceticacid, the corresponding 4-NH analog 9a, is produced which can becatalytically hydrogenated to yield the7-beta-ethyl-5α-4-aza-cholestan-3-one, 10a.

The above defined 7-substituents can be introduced into all of thecompounds defined for the 17-A group herein by appropriate analogousprocedures.

The following examples are illustrative of representative embodiments ofthis invention and should not be construed to be limits on the scope orspirit of the instant invention.

The Rf values cited were carried out on standard thin layerchromatographic Si gel plates. The elution solvent system used is givenin the parentheses following the Rf value.

The mass spectral values are given either as FAB, i.e., fast atombombardment, and are reported as (M+1) molecular ion peaks, being themolecular weight plus one atomic mass unit. The electron impact (EI)mass spectrum values are reported as molecular ion peaks and areindicated in parentheses, either being (M) or (M+2), the molecularweight, MW, or the MW plus two atomic units.

The nuclear magnetic resonance data was taken at 400 MHz in CDCl₃ and istabulated for unique proton values of each compound at the end of theExamples. The coupling constant J is given in Hertz (Hz) units.

EXAMPLE 1 Synthesis of 3-Acetoxy-Androst-5-en-17-ol (2)

To a solution of 100 mg. (0.303 mmol) of 3-acetoxy-androst-5-en-17-one,1, in 3 ml EtOH at -10° C., was added 22.9 mg (0.606 mmol) of sodiumborohydride with stirring. After the reaction mixture was stirred forone and 1/2 hours, the mixture was diluted with 10 ml water, the ethanolsolvent removed under vaccum, and the residue extracted with ethylacetate. The organic layer was washed with aqueous Na₂ CO₃, brine, driedover sodium sulfate and concentrated to leave a residue of crude titlecompound 2. Proton NMR confirmed the assigned structure.

EXAMPLE 2 Synthesis of 3-Acetoxy-Androst-5-en-17-ol,17-t-butyl-dimethylsilyl ether (3)

To a solution of the androstan-17-ol, 2 from Example 1, being 4.5 g(13.55 mmol) in 50 ml. dimethylformamide at 23° C. was added 2.76 g(40.65 mmol) imidazole followed by 3.063 g (20.32 mmol) oft-butyldimethylsilyl chloride. The reaction mixture was stirred and asolid began to precipitate. Twenty additional ml of DMF were added wasand the mixture further stirred overnight. The mixture was poured into 1liter water, the solid filtered and washed with water. The solid wasdissolved in ethylacetate, the organic layer washed with brine and driedover sodium sulfate, concentrated to yield the silyl protected 7-oltitle compound 3. The proton NMR confirmed the assigned structure.

EXAMPLE 3 Synthesis of 3-Acetoxy-Androst-5-ene-7-one-17β-ol,17-t-butyldimethylsilyl ether (4)

To a solution of the TBMS protected 17-ol 3 from Example 2, being 5.6 g(12.55 mmol) in 100 ml acetonitrile at 23° C. was added 90% t-butylhydrogen peroxide, 3.958 g (43.92 mol), and 138 mg chromiumhexacarbonyl. After refluxing the mixture under nitrogen for 24 hours,the reaction mixture was poured into one liter water, solid wasfiltered, the residue washed with 500 ml water and the residue dissolvedin 350 ml methylene chloride. The organic layer was washed with brine,dried over sodium sulfate and concentrated to yield crude material. Thinlayer chromatography (3:1 hexane/ethyl acetate on silica gel) showed thepresence of starting material. The solid was purified by columnchromatography over silica gel by elution with 7% ethyl acetate/hexaneto yield the title compound 4. Proton NMR confirmed the assignedstructure.

EXAMPLE 4 Synthesis of 3,7-Dihydroxy-7-methyl-Androst-5-en-17β-ol,17-TBMS ether (5)

To a solution of the product 4 from Example 3, being 440 mg. (0.956mmol) in dry tetrahydrofuran at 0° C. was added dropwise methylmagnesium chloride over 5-10 minutes. The reaction mixture was thenallowed to stir at room temperature for 24 hours, then poured intosaturated aqueous ammonium chloride. The THF solvent was removed undervacuum and the aqueous phase extracted with ethyl acetate. The organiclayer was washed with brine, dried, concentrated to yield crude product.Proton NMR confirmed the assigned structure of the title compound 5which was used in the next step without further purification.

EXAMPLE 5 Synthesis of 7-methyl-Androst-4,6-dien-3-one-17-ol,17-t-butyldimethylsilyl ether (6)

The above Grignard product 5, 3.5 g. (7.142 mmol) was dissolved in 50 mltoluene/50 ml. cyclohexanone and 20 ml of solvent distilled off undervacuum. To this was added 4.54 g. aluminum isopropoxide and the reactionmixture refluxed overnight for 15 hours. The mixture was cooled, dilutedwith ethyl acetate, washed with sodium potassium tartarate, brine, andthe organic layer was concentrated under vacuum and the residue steamdistilled. The residue was extracted with ethyl acetate, washed withbrine, dried and purified by column chromatography on silica gel,eluting with 5% EtOAc/hexane to yield the title compound 6.

EXAMPLE 6 Synthesis of 7β-Methyl-Androst-5-en-3-one-17-ol,t-Butyldimethylsilyl ether, (7)

To a solution of 370 mg of 6, from Example 5, in 5.5 ml ammonia, 1 mlTHF, 1 ml. toluene, was added 50 mg. of metallic lithium in smallpieces. After stirring the blue solution for 2 hours, a solution of1,2-dibromethane in 2 ml THF was added. After stirring the solution at-78° C. for 10 minutes, 250 mg of ammonium chloride was added and themixture stirred for 10 minutes. The excess ammonia was removed byevaporation under a nitrogen steam. The reaction mixture was dilutedwith brine, extracted with ethyl acetate. The organic layer was washedwith brine, dried and concentrated to yield crude material 7 which wasused as such in Example 7.

EXAMPLE 7 Synthesis of 7β-Methyl-Androst-4-en-3-on-17-ol,t-Butyldimethylsilyl ether, (8)

To a solution of 7, from Example 6, being 432 mg in 4 ml THF was added150 microliters DBU (1,8-diazabicyclo[5.4,0]undec-7-ene under nitrogenwith stirring. The mixture was refluxed for 1.5 hours, then cooled,diluted with NH₄ Cl solution. The solvent THF was removed under vacuumand the residue extracted with ethyl acetate. The organic layer waswashed with brine, dried and concentrated under reduced pressure toyield crude material. The titled product 8 was purified bychromatography on silica gel using 10% EtOAc/hexane as eluant.

EXAMPLE 8 Synthesis of17β-(t-butyldimethylsilyloxy)-7β-methyl-5-oxo-A-nor-3,5-secoandrostan-3-oicacid, (9)

To a solution of 884 mg of 8 in 15 ml. t-butyl alcohol at 80° C. wasadded 248 mg sodium carbonate in 1.5 ml water followed by a dropwiseaddition over 15-20 minutes of a mixture of 2.273 g sodium periodatewith 16.8 mg potassium permanganate in 8 ml. water. The reaction mixturewas heated at 80° C. for 2 hours, cooled, filtered, the residue washedwith water, and then the extract concentrated under vaccum. The extractwas acidified with aqueous HCl, extracted with ethyl acetate and theorganic layer washed with aqueous NaHSO₃, brine, dried and concentratedto yield crude 9. The proton NMR confirmed the assigned structure.

EXAMPLE 9 Synthesis of 4,7-Dimethyl-4-aza-Androst-5-en-3-one-17-ol,t-butyldimethylsilyl ether, (10)

To a solution of 9, 840 mg in 5 ml ethylene glycol was added 1.5 gsodium acetate and 737 mg. methylamine hydrochloride. After stirring thereaction mixture 4 hours at 180° C., the mixture was cooled, dilutedwith water, extracted with ethyl acetate, dried and concentrated toafford crude title compound 10. Proton NMR confirmed the assignedstructure.

EXAMPLE 10 Synthesis of 4,7-Dimethyl-4-aza-Androst-5-en-3-one-17-ol,(11)

To a solution of 700 mg of 10 from Example 9, in 20 ml of acetonitrileat 0° C. was added 500 microliters aqueous HF. After stirring thereaction mixture for one hour, the HF was neutralized with aqueoussodium carbonate, diluted with water, acetonitrile removed under vacuum,and the residue extracted with ethyl acetate. The organic layer wasdried, concentrated to give crude title compound 11 which was furtherpurified by preparative chromatography on silica gel using 3:1chloroform/acetone.

EXAMPLE 11 Synthesis of 4,7-dimethyl-4-aza-androstan-3-one-17-ol, (12)

To a solution of 11 from Example 10, being 350 mg in 10 ml acetic acidwas added 100 mg catalytic platinum dioxide and the resulting mixturewas evacuated and flushed with hydrogen. The reaction was shakenovernight at room temperature under 40 Psig hydrogen pressure. Thesolution was filtered and concentrated to a residue. The residue wasworked up with ethyl acetate, the organic layer was then concentratedunder vacuum, diluted with ethyl acetate, washed with aqueous NaHCO₃,brine, dried, concentrated to yield the title compound 12. Mass Spec:320, (M+1).

The following Table lists the unique proton NMR values (400 MHz inCDCl₃) for each compound. The data are reported as: s=singlet,d=doublet, m=multiplet, J=coupling constant. The absorption values aregiven del (δ) units and are illustrated for the C-18, C-19 and C-21angular ring methyl protons and protons associated with unique portionsof the molecule.

The numbering of the steriod is given by the following structure:##STR16##

    ______________________________________                                        NMR DATA                                                                      Compound                                                                      No.      C-18 CH.sub.3                                                                           C-19 CH.sub.3                                                                             Others                                         ______________________________________                                        2        0.72      1.02        3 OAc, 3H, s, 2.02                                                            17H, 1H, t, 3.65                                                              J=8.5                                          3        0.70      1.02        3 OAc, 3H, s, 2.02                                                            17H, 1H, t, 3.55,                                                             J=8.5                                          4        0.72      1.21        3 OAc, 3H, s, 2.04                                                            17H, 1H, t, 3.55                                                              J=8.5                                          5        0.72      0.95        7 Me, 3H, s, 1.12                                                 1.20        1.21                                                                          17H, 1H, m, 3.55                               6        0.80      1.08        7 Me, 3H, s, 1.9                                                              6H, 1H, s, 5.68                                                               4H, 1H, s, 5.92                                7        0.72      1.12        7 Me, 3H, d, 0.96                                                             J=6.6                                                                         6H, 1H, m, 5.08                                8        0.72      1.17        7 Me, 3H, d, 1.03                                                             J=6.5                                                                         4H, 1H, s, 5.68                                9        0.72      1.04        7 Me, 3H, d, 0.95                                                             J=6.5                                          10       0.72      1.02        7 Me, 3H, d, 1.04                                                             J=6.5                                                                         6H, 1H, d, 4.78                                                               J=3                                            11       0.78      1.02        7 Me, 3H, d, 1.06,                                                            J=6.5                                                                         6H, 1H, d, 4.79,                                                              J=3                                            12       0.74      0.86        7 Me, 3H, d, 1.02,                                                            J=6.5                                                                         5H, 1H, dd, 3.10                                                              J=4.5                                                                         J=13.5                                          8a      0.690     0.830       21-CH.sub.3, d, 0.900                                                         J=7                                                                           N-CH.sub. 3, s, 2.93                           10a      0.675     0.808       21-CH.sub.3, d, 0.893                                                         J=7                                                                           5H, m, 2.97-3.13                               ______________________________________                                    

What is claimed is:
 1. A process for the synthesis of 7β-Substituted4-aza-5α-androstan-3-ones, comprising the steps of (a) oxidizing acompound of the formula ##STR17## where Alk is selected from the groupconsisting of C1-4 alkyl, allyl and C3-6 cycloalkyl; and where A isselected from the group consisting of hydrogen, dimethyl-t-butylsilyloxy, hydroxy, acetylamino, amino, C1-10 alkyl, stigmasterol, phenylsubstituted C1-10 alkyl, pyridyl substituted C1-10 alkyl, C1-10carboalkoxy, C1-10 alkylcarboxamide, carboxy, and C1-10alkylcarbonylamino urea; said compound oxidized in the presence ofaluminum isopropoxide and cyclohexanone to form a compound of theformula ##STR18## (b) contacting the product of step (a) with a reducingsystem comprised of metallic lithium and liquid ammonia in an inertorganic solvent therefor at a temperature in the range of about -45° to-78° for a sufficient time to stereo-selectively produce the 7β compoundof the formula: ##STR19## (c) contacting the product of step (b) with adouble bond isomerization agent selected from the group consisting of1,8-diazabicyclo[5.4.0]undec-7-ene, diisopropylethylamine anddiazabicyclo[4.3.0]non-5-ene, in an inert organic solvent therefor, at atemperature of 40° to 65°, under conditions in which the radical A isinert, for a sufficient time to form the isomerized compound of theformula: ##STR20## (d) contacting the product of step (c) with anoxidizing agent selected from the group consisting of potassiumpermanganate, sodium periodate, ruthenium tetraoxide and ozone; in aninert solvent therefor, at a temperature in the range of 23° to 80°under conditions in which radical A is inert, for a sufficient time toform the seco acid of the formula: ##STR21## (e) contacting the productof step (d) with an amine of the formula R--NH₂, wherein R is H, C1-4alkyl, benzyl or allyl, at a temperature of from 100° to 200° in aninert solvent therefor, under conditions in which A is inert, to formthe 4-aza-steroid of the formula: ##STR22## (f) and contacting theproduct of step (e) with a platinum catalyst in an inert organicsolvent, at room temperature, under conditions where A is inert, for asufficient time to form the 7-Alk-4-aza steroid of the formula:##STR23##
 2. The process of claim 1 in which Alk is methyl.
 3. Theprocess of claim 1 in which the reducing system is comprised of metalliclithium and liquid ammonia.